Neuronal Kmt2a/Mll1 Histone Methyltransferase Is Essential for Prefrontal Synaptic Plasticity and Working Memory

• DOI: 10.1523/jneurosci.3004-14.2015
• Publication Date: 2015-04-01T16:52:02Z
• Authors: Mira Jakovcevski; Hongyu Ruan; Erica Y. Shen; Aslihan Dincer; Behnam Javidfar; Qi Ma; Cyril J. Peter; Iris Cheung; Amanda C. Mitchell; Yan Jiang; Cong L. Lin; Venu Pothula; A. Francis Stewart; Patricia Ernst; Wei-Dong Yao; Schahram Akbarian
• Keywords: Homeodomain Proteins; Male; 0301 basic medicine; Neuronal Plasticity; Behavior, Animal; Pyramidal Cells; Gene Expression; Prefrontal Cortex; Mice, Transgenic; Nerve Tissue Proteins; Histone-Lysine N-Methyltransferase; Methylation; Cytoskeletal Proteins; Mice; 03 medical and health sciences; Memory, Short-Term; Prosencephalon; Gene Knockdown Techniques; Mutation; Animals; Myeloid-Lymphoid Leukemia Protein

Neuronal histone H3-lysine 4 methylation landscapes are defined by sharp peaks at gene promoters and other cis -regulatory sequences, but molecular cellular phenotypes after neuron-specific deletion of H3K4 methyl-regulators remain largely unexplored. We report that neuronal ablation the H3K4-specific methyltransferase, Kmt2a/Mixed-lineage leukemia 1 ( Mll1 ), in mouse postnatal forebrain adult prefrontal cortex (PFC) is associated with increased anxiety robust cognitive deficits without locomotor dysfunction. In contrast, only mild behavioral were observed ortholog Kmt2b/Mll2 PFC. Impaired working memory Kmt2a/Mll1 PFC neurons was loss training-induced transient waves Arc immediate early expression critical for synaptic plasticity. Medial layer V pyramidal neurons, a major output relay cortex, demonstrated severely impaired facilitation temporal summation, two forms short-term plasticity essential memory. Chromatin immunoprecipitation followed deep sequencing -deficient cortical revealed downregulated transcriptional mark, trimethyl-H3K4, <50 loci, including homeodomain transcription factor Meis2 . Small RNA-mediated knockdown defects similar to those elicited deletion. Therefore, mature critically depend on maintenance -regulated subset genes an role cognition emotion.